Multiple colon carcinomas in a patient with Cowden syndrome

Cowden syndrome is a non-adenomatous gastrointestinal polyposis syndrome with inactivation of PTEN, a dual-phosphatase tumor suppressor gene. Patients with loss of wildtype PTEN expression from one allele carry an increased risk of malignant breast, thyroid and brain tumors. However, the risk of malignant transformation in gastrointestinal polyps is still unclear. In this study, we describe a kindred with Cowden syndrome and identify a heterozygous germline mutation causing truncation of the PTEN tumor suppressor. The index patient was a 56 year-old woman having multiple facial papules, acral keratosis, oral papillomatosis, multiple benign breast and thyroid tumors and gastrointestinal polyposis. Progression to invasive adenocarcinoma occured in two pre-existing hamartomatous polyps. Analysis of one of the carcinomas revealed somatic inactivation of the wildtype PTEN allele by exon-skipping. This case demonstrates that gastrointestinal hamartomas in Cowden syndrome patients can progress to invasive adenocarcinomas and should therefore be carefully monitored.